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Fraisinib: a calix[4]pyrrole derivative effective in reducing NSCLC tumor in-vivo, is found to act as ligand of the Glycine-tRNA Synthase (GARS1), a new molecular target in oncology.

ABSTRACT: Adopting a multi-proteomic approach, we evaluated the possible involvement of GARS1 in the regulation of phenotypic alterations that reduced in vivo tumorigenicity of A549 cells exposed to Fraisinib over time. For this purpose, we performed a differential proteomic analysis followed by the generation of functional networks and enrichment analysis, and then we compared the obtained results after including the known GARS1 interactors identified in A549 cell line.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung, Epithelial Cell

DISEASE(S): Lung Cancer

SUBMITTER: Gabriela Coronel Vargas

LAB HEAD: Camillo Rosano

PROVIDER: PXD037653 | Pride | 2024-01-20

REPOSITORIES: Pride

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			Action	DRS
	2022_07_18_Calixpirroli_A549_differentTime_forPubblication.msf	Msf
	2022_07_18_Calixpirroli_A549_differentTime_forPubblication_InputFiles.txt	Txt
	2022_07_18_Calixpirroli_A549_differentTime_forPubblication_PSMs.txt	Txt
	2022_07_18_Calixpirroli_A549_differentTime_forPubblication_Proteins.txt	Txt
	851_31052022.raw	Raw

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Project description:Individuals with hepatic steatosis often display several metabolic abnormalities including insulin resistance and muscle atrophy. Previously, we found that hepatic steatosis results in an altered hepatokine secretion profile, thereby inducing skeletal muscle insulin resistance via inter-organ crosstalk. In this study, we aimed to investigate whether the altered secretion profile in the state of hepatic steatosis also induces skeletal muscle atrophy via effects on muscle protein turnover. To investigate this, eight-week-old male C57BL/6J mice were fed a chow (4.5% fat) or a high-fat diet (HFD; 45% fat) for 12 weeks to induce hepatic steatosis, after which the livers were excised and cut into ~200 µm slices. Slices were cultured to collect secretion products (conditioned medium; CM). Differentiated L6-GLUT4myc myotubes were incubated with chow or HFD CM to measure glucose uptake. Differentiated C2C12 myotubes were incubated with chow or HFD CM to measure protein synthesis and breakdown, and gene expression via RNA sequencing. Furthermore, proteomics analysis was performed in chow and HFD CM. It was found that HFD CM caused insulin resistance in L6-GLUT4myc myotubes compared with chow CM, as indicated by a blunted insulin-stimulated increase in glucose uptake. Furthermore, protein breakdown was increased in C2C12 cells incubated with HFD CM, while there was no effect on protein synthesis. RNA profiling of C2C12 cells indicated that 197 genes were differentially expressed after incubation with HFD CM, compared with chow CM, and pathway analysis showed that pathways related to anatomical structure and function were enriched. Proteomic analysis of the CM showed that 32 proteins were differentially expressed in HFD CM compared with chow CM. Pathway enrichment analysis indicated that these proteins had important functions with respect to insulin-like Growth Factor transport and uptake, and affect post-translational processes, including protein folding, protein secretion and protein phosphorylation. In conclusion, the results of this study support the hypothesis that secretion products from the liver contribute to the development of muscle atrophy in individuals with hepatic steatosis.

Dataset Information

Fraisinib: a calix[4]pyrrole derivative effective in reducing NSCLC tumor in-vivo, is found to act as ligand of the Glycine-tRNA Synthase (GARS1), a new molecular target in oncology.

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